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Biomedical subjects

R B Innis

Publications and source records attributed to R B Innis.

At least 37 records · Page 2Linked to original sources
PubMed2000

Prediction of dopamine transporter binding availability by genotype: a preliminary report.

OBJECTIVE: Evidence of a relationship between genotype and binding availability was assessed for the dopamine and serotonin transporter genes. METHOD: The authors assessed dopamine transporter genotype at the SLC6A3 3' variable number of tandem repeats (VNTR) polymorphism and serotonin transporter genotype at the SLC6A4 promotor VNTR polymorphism in 30 healthy subjects who also underwent single photon emission computed tomography with [(123)I]beta-CIT. RESULTS: Subjects homozygous for the 10-repeat allele at the SLC6A3 locus demonstrated significantly lower dopamine transporter binding than carriers of the nine-repeat allele. There was no effect of SLC6A4 genotype upon serotonin transporter binding. CONCLUSIONS: These findings suggest that genetic variation at the SLC6A3 3' VNTR polymorphism may modify dopamine transporter function.

Adult↗
PubMed2000

Brain SPECT imaging of amphetamine-induced dopamine release in euthymic bipolar disorder patients.

OBJECTIVE: Increased dopaminergic neurotransmission has been implicated in the pathophysiology of bipolar disorder. However, it remains unclear whether the abnormality is due to increased dopamine release or enhanced postsynaptic receptor sensitivity. In this study, dopamine receptor imaging combined with a pharmacological challenge of amphetamine was used to assess both pre- and postsynaptic aspects of dopamine neurotransmission in euthymic bipolar disorder patients. METHOD: Thirteen patients with bipolar disorder (seven medication free and six receiving mood stabilizer therapy) who had been euthymic for more than 4 weeks and 13 age- and gender-matched healthy comparison subjects were included in the study. Single photon emission computed tomography scans were obtained with the striatal dopamine (D(2)/D(3)) receptor radiotracer iodobenzamide ([(123)I]IBZM) before and after an intravenous amphetamine challenge (0.3 mg/kg). Reduction in striatal [(123)I]IBZM binding potential from the first scan to the second scan was used as an indirect measure of the amount of dopamine released. Behavioral response to amphetamine was measured with the Brief Psychiatric Rating Scale, Young Mania Rating Scale, and visual analogue scales. RESULTS: Bipolar patients and healthy subjects did not differ in terms of mood state or striatal D(2) receptor binding at baseline. Amphetamine challenge led to a significantly greater behavioral response in bipolar patients than in healthy subjects. However, there was no significant difference between the two groups in the amphetamine-induced decrease in striatal [(123)I]IBZM binding. CONCLUSIONS: In a group of euthymic patients with bipolar disorder, this study did not find evidence for increased striatal dopamine release. Instead, these data are consistent with enhanced postsynaptic dopamine responsivity in patients with bipolar disorder.

Adult↗
PubMed2000

Decreased benzodiazepine receptor binding in prefrontal cortex in combat-related posttraumatic stress disorder.

OBJECTIVE: Animals exposed to stress exhibit a decrease in benzodiazepine receptor binding in the frontal cortex. No studies have examined central benzodiazepine receptor binding in patients with posttraumatic stress disorder (PTSD). The purpose of this study was to examine measures of benzodiazepine receptor binding in PTSD. METHOD: From 13 patients with Vietnam combat-related PTSD and 13 case-matched healthy comparison subjects, a quantitative measure related to benzodiazepine receptor binding (distribution volume) was obtained with single photon emission computed tomography (SPECT) imaging of [(123)I]iomazenil binding and measurement of radioligand concentration in plasma. Distribution volume image data were analyzed by means of statistical parametric mapping. RESULTS: Lower distribution volumes were found in the prefrontal cortex (Brodmann's area 9) of PTSD patients than in comparison subjects. CONCLUSIONS: These findings of lower values for the benzodiazepine receptor binding measure of distribution volume are consistent with fewer benzodiazepine receptors and/or reduced affinity of receptor binding in the medial prefrontal cortex in patients with PTSD. Alterations in benzodiazepine receptor function in this area may underlie many of the symptoms of PTSD.

Adult↗
PubMed2000

Elevated central serotonin transporter binding availability in acutely abstinent cocaine-dependent patients.

OBJECTIVE: Recent work has underscored the role of serotonergic neurotransmission in chronic neural adaptations to cocaine dependence. The authors tested for evidence of serotonergic dysfunction during acute abstinence from cocaine, a period of high risk for relapse in cocaine dependence. METHOD: Binding availability of dopamine transporters and serotonin transporters was measured in 15 cocaine-dependent subjects during acute abstinence and in 37 healthy comparison subjects by using [(123)I]beta-CIT and single photon emission computed tomography. RESULTS: Significant increases in diencephalic and brainstem serotonin transporter binding (16.7% and 31.6%, respectively) were observed in cocaine-dependent subjects. Brainstem serotonin transporter binding was significantly inversely correlated with age across diagnostic groups. CONCLUSIONS: These findings provide further evidence of serotonergic dysfunction during acute abstinence from chronic cocaine use. Age-related decline in brainstem serotonin transporter binding may underlie the poor response to selective serotonin reuptake inhibitor antidepressants seen in some elderly depressed patients.

Adult↗
PubMed2000

PET quantification of 5-HT2A receptors in the human brain: a constant infusion paradigm with [18F]altanserin.

UNLABELLED: [18F]altanserin has been used to label serotonin 5-HT2A receptors, which are believed to be important in the pathophysiology of schizophrenia and depression. The purpose of this study was to test the feasibility of a constant infusion paradigm for equilibrium modeling of [18F]altanserin with PET. Kinetic modeling with [18F]altanserin may be hampered by the presence of lipophilic radiometabolites observed in plasma after intravenous administration. METHODS: Eight healthy volunteers were injected with [18F]altanserin as a bolus (208+/-9 MBq [5.62+/-0.25 mCi]) plus constant infusion (65+/-3 MBq/h [1.76+/-0.08 mCi/h]) ranging from 555 to 626 min (615+/-24 min) after injection. PET acquisitions (10-20 min) and venous blood sampling were performed every 30-60 min throughout the infusion period. RESULTS: Linear regression analysis revealed that time-activity curves for both brain activity and plasma [18F]altanserin and metabolite concentrations stabilized after about 6 h. This permitted equilibrium modeling and estimation of V3' (ratio of specific uptake [cortical-cerebellar] to total plasma parent concentration after 6 h). Values of V3' ranged from 1.57+/-0.38 for anterior cingulate cortex to 1.02+/-0.39 for frontal cortex. The binding potential V3 (ratio of specific uptake to free plasma parent concentration after 6 h, using group mean f1) was also calculated and ranged from 169+/-41 for anterior cingulate cortex to 110+/-42 for frontal cortex. From 6 h onward, the rate of change for V3' and V3 was only 1.11+/-1.69 %/h. CONCLUSION: These results demonstrate the feasibility of equilibrium imaging with [18F]altanserin over more than 5 radioactive half-lives and suggest a method to overcome difficulties associated with lipophilic radiolabeled metabolites. The stability in V3 and V3' once equilibrium is achieved suggests that a single PET acquisition obtained at 6 h may provide a reasonable measure of 5-HT2A receptor density.

Adult↗
PubMed2000

Test-retest reproducibility of extrastriatal dopamine D2 receptor imaging with [123I]epidepride SPECT in humans.

UNLABELLED: This study evaluated the test-retest reproducibility of D2 receptor quantification in the thalamus and temporal cortex using [123I]epidepride SPECT. METHODS: Ten healthy volunteers (4 men, 6 women; age range, 19-46 y) underwent 2 SPECT studies (interval, 2-26 d) using a bolus-plus-constant-infusion paradigm (bolus-to-infusion ratio = 6 h; infusion time = 9 h). Plasma clearance (in liters per hour) and free fraction (f1) of the parent tracer were measured. Radioactivity (in becquerels per gram) in the thalamus, temporal cortex, and cerebellum were normalized to the infusion rate (in becquerels per hour). Normalized striatal radioactivity was also measured to assess reproducibility in regions with a high density of receptors and better counting statistics. The outcome measures obtained were V3 (receptor density [Bmax]/equilibrium dissociation constant [KD]), V3' (f1 x Bmax/KD), and RT (specific-to-nondisplaceable tissue ratio). RESULTS: Test-retest variability and reliability (intraclass correlation coefficient) were 10.8% and 0.88, respectively, for plasma clearance and 15.3% and 0.77, respectively, for f1. The test-retest variability of brain-specific (target minus nondisplaceable) radioactivity was higher in the thalamus and temporal cortex than in the striatum, although reliability was comparable. Among the outcome measures, V3' showed better test-retest variability and reliability in the thalamus (13.3% and 0.75, respectively) and temporal cortex (13.4% and 0.86, respectively). CONCLUSION: Brain radioactivity was the main source of variability for quantification of extrastriatal D2 receptors with [123I]epidepride. The reproducibility of outcome measures in extrastriatal regions was good. However, because receptor density was lower in extrastriatal regions than in the striatum, the counting statistics in these regions were low and reproducibility was affected by the higher test-retest variability of brain-specific radioactivity. Compared with V3 and V3', RT showed less test-retest variability in the thalamus and temporal cortex but lower reliability. Moreover, measurement of RT may be affected by the presence of potential lipophilic metabolites entering the brain.

Adult↗
PubMed2000

Measurement of alpha4beta2 nicotinic acetylcholine receptors with [123I]5-I-A-85380 SPECT.

UNLABELLED: Nicotinic acetylcholine receptors (nAChRs) play an important role in tobacco dependence and a potential therapeutic role in neuropsychiatric disorders such as Alzheimer's disease. [123I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) is a new SPECT tracer that labels alpha4beta2 nAChRs. The purpose of this study was to assess the usefulness of this tracer to measure regional nAChR binding in baboon brain using both a bolus/kinetic paradigm and also a bolus plus constant infusion/equilibrium paradigm. METHODS: A pair of bolus/kinetic and bolus plus constant infusion/equilibrium studies was performed in each of 3 isoflurane-anesthetized baboons. Bolus studies were performed by intravenous injection of 191-226 MBq [123I]5-I-A-85380 and image acquisition for 289-367 min. The data were analyzed with 1- and 2-tissue compartment models. Bolus plus constant infusion/equilibrium studies were performed by a bolus injection (74-132 MBq) followed by a 468- to 495-min infusion with a bolus/infusion ratio (B/I) of 4.8-5.0 h. The distribution volumes in the thalamus were measured in these 2 paradigms. To study whether the cerebellum was appropriate as a receptor-poor region, displacement studies were done in 2 baboons using the B/I paradigm with subcutaneous injection of (-)-cytisine (0.8 and 1.0 mg/kg). RESULTS: The kinetics of this tracer was best described by the 1-tissue compartment model. The 2-compartment model showed poor identifiability of rate constants. The total (specific plus nondisplaceable compartments) distribution volumes (V(T)') agreed between bolus and B/I paradigms (average percentage difference in V(T)', 16.8%). (-)-Cytisine (0.8 and 1.0 mg/kg) displaced 70% and 72% of the radioactivity in the thalamus and 36% and 55% in the cerebellum, respectively, indicating that the latter was not appropriate as a receptor-poor region. CONCLUSION: These results show the feasibility of quantifying alpha4beta2 nAChRs using [123I]5-I-A-85380 and support the use of V(T)' as an appropriate outcome measure.

Alkaloids↗
PubMed1999

Kinetic and equilibrium analyses of [(123)I]epidepride binding to striatal and extrastriatal dopamine D(2) receptors.

Quantitative SPECT measures of dopamine D(2) like receptors with [(123)I]epidepride is complicated by its high affinity and lipophilic metabolites. The purpose of this study was to use both parent (P) and lipophilic metabolites (M) as input functions in a kinetic paradigm and in comparison to the results of equilibrium studies. Kinetic studies on eleven healthy human subjects, ages 32+/- 10 were performed following i.v. injection of approximately 370 MBq of [(123)I]epidepride. Images were acquired for 13.5+/-1.0 hours. Equilibrium studies were done on seven of eleven subjects with a bolus injection of approximately 140 MBq, bolus/infusion ratio of 10 hours, and infusion for 30-32 hours. High (striatum) and low (temporal cortex) density regions were studied. Two (P and M) and one (P) input function models were applied in the kinetic studies. In receptor-rich regions, the distribution volumes in nondisplaceable compartments were fixed to those in cerebellum. In addition, in the two input function model, K(1)(P)/K(1)(M) was fixed to the values in the cerebellum. The one input function model provided V'(3) values (=f(1)*B'(max)/K(D)) which were consistent with those obtained in equilibrium studies in both receptor-rich regions, while the two input function model provided consistent values only in striatum. Poor identifiability of the rate constants of metabolites seemed to be the source of errors in the two input function model. These results suggest that correct V'(3) values can be obtained with the one input function model both in high- and low-density regions.

Adult↗
PubMed1999

[123I]Iomazenil SPECT benzodiazepine receptor imaging in schizophrenia.

Deficient inhibitory neurotransmission of gamma-aminobutyric acid (GABA) has been implicated in the pathophysiology of schizophrenia based on postmortem studies. However, in vivo studies have shown predominantly negative or conflicting results. The goal of this study was to better characterize possible changes of the regional GABA(A)-benzodiazepine receptor distribution volume (BZR V3-p) in schizophrenia in vivo, using a larger sample size than previous studies. Single photon emission computed tomography (SPECT) with [123I]iomazenil was used with a constant infusion paradigm to measure the BZR V3-p under sustained radiotracer equilibrium conditions. Twenty-five patients with schizophrenia and 24 matched healthy control subjects were studied. Positive and Negative Syndrome Scale (PANSS) ratings were done in all subjects. Statistical parametric mapping (SPM) 96 was used to compare patients and control subjects as well as to study the relationship between SPECT results and composite PANSS scores based on two factorial models: the pentagonal model (positive, negative, dysphoric mood, activation, and autistic preoccupation factors) and the taxometric model (disorganized dimension). On the basis of 'absolute' values of V3-p with no normalization for total brain uptake, the schizophrenic patients showed no significant differences in BZR levels compared to the healthy control subjects. With a global normalization procedure, which is more sensitive to relative regional differences in activity, BZR V3-p was significantly decreased in the patients in the left precentral gyrus (BA 6). The relative BZR V3-p showed a significant positive correlation with duration of illness in the superior occipital gyri (BA 19). No significant correlations were observed between either absolute or relative BZR V3-p and either age or any of the composite PANSS scores based on any of the two factorial models in either patients or control subjects. No significant differences were observed between cigarette smoking vs. non-smoking patients, nor between the patients on atypical antipsychotics vs. on typical antipsychotics vs. not on any antipsychotics. In general, no significant differences in BZR V3-p were observed between patients and control subjects, except for a decrease in relative BZR V3-p in the left precentral gyrus. Grey matter atrophy is unlikely to be the cause for this decrease. However, we could not exclude that possibility. The positive correlation with duration of illness might reflect the relative preservation of neurons expressing BZR in the superior occipital gyri as compared to other cortical brain regions in schizophrenia.

Adult↗
PubMed1999

Neurochemical brain imaging investigations of schizophrenia.

Neurochemical brain imaging methods developed over the past 20 years offer significant promise for elucidating the biochemical underpinnings of schizophrenia. The two general methodologies used for these studies have been: 1) radiotracer imaging: PET (positron emission tomography) and SPECT (single photon emission computed tomography); and 2) NMR (nuclear magnetic resonance) imaging: fMRI (functional magnetic resonance imaging) and MRS (magnetic resonance spectroscopy). Despite conflicting findings, striatal D2 receptor density may be elevated in some, but not all patients. Elevated synthesis, and increased release of dopamine after amphetamine challenge have also been reported. Imaging of cortical 5-HT2A receptors suggests that this system is unaffected, in conflict with findings of postmortem studies. Although prior postmortem studies suggested an increase in cortical GABAA receptors, three SPECT studies have found no significant changes. MRS studies have shown decreased levels of NAA (N-acetyl-aspartate) moieties in hippocampus and frontal cortex of schizophrenic patients, which is consistent with the reported loss of neurons and neuropil in postmortem brains. In conclusion, developments in radiotracer and NMR imaging have provided promising leads to the biochemical abnormalities associated with schizophrenia. Future significant understanding is likely to occur with the development of new probes and enhanced instrument technology, when applied with an appreciation of the heterogeneity of the disorder and the need for careful clinical assessment of patients.

Aspartic Acid↗
PubMed1999

Quantitation of benzodiazepine receptor binding with PET [11C]iomazenil and SPECT [123I]iomazenil: preliminary results of a direct comparison in healthy human subjects.

Although positron emission tomography (PET) and single photon emission computed tomography (SPECT) are increasingly used for quantitation of neuroreceptor binding, almost no studies to date have involved a direct comparison of the two. One study found a high level of agreement between the two techniques, although there was a systematic 30% increase in measures of benzodiazepine receptor binding in SPECT compared with PET. The purpose of the current study was to directly compare quantitation of benzodiazepine receptor binding in the same human subjects using PET and SPECT with high specific activity [11C]iomazenil and [123I]iomazenil, respectively. All subjects were administered a single bolus of high specific activity iomazenil labeled with 11C or 123I followed by dynamic PET or SPECT imaging of the brain. Arterial blood samples were obtained for measurement of metabolite-corrected radioligand in plasma. Compartmental modeling was used to fit values for kinetic rate constants of transfer of radioligand between plasma and brain compartments. These values were used for calculation of binding potential (BP = Bmax/Kd) and product of BP and the fraction of free non-protein-bound parent compound (V3'). Mean values for V3' in PET and SPECT were as follows: temporal cortex 23+/-5 and 22+/-3 ml/g, frontal cortex23+/-6 and 22+/-3 ml/g, occipital cortex 28+/-3 and 31+/-5 ml/g, and striatum 4+/-4 and 7+/-4 ml/g. These preliminary findings indicate that PET and SPECT provide comparable results in quantitation of neuroreceptor binding in the human brain.

Adult↗
PubMed1999

Changes of benzodiazepine receptors during chronic benzodiazepine administration in humans.

Changes of central type GABA(A)/benzodiazepine receptors during 24-day per-oral administration of alprazolam (2 mg/day) were measured with single photon emission computed tomography (SPECT) in nine healthy human subjects. Receptor densities were measured on days -4 (baseline), 3, 10, 17 and 24. Comparison of baseline and day 3 SPECT images was used to assess receptor occupancy; comparisons of the four scans on medication were used to assess alterations in receptor levels. Clinical effects were evaluated by subjective ratings of mood and the Hopkins verbal learning test. Alprazolam induced sedation associated with a 16% receptor occupancy. Unoccupied receptor levels decreased 10% from day 3 to day 10 but then normalized to baseline values by day 17. Clinical effects showed corresponding changes 1-2 weeks after the changes in the receptor. Thus, the decrease of benzodiazepine receptor densities may be one of the major mechanisms for tolerance development in humans.

Administration, Oral↗
PubMed1999

Effect of treatment with L-dopa/carbidopa or L-selegiline on striatal dopamine transporter SPECT imaging with [123I]beta-CIT.

The effect of subchronic treatment with L-dopa/carbidopa or L-selegiline on striatal dopamine transporters (DAT) was examined in patients with idiopathic Parkinson's disease with SPECT (single photon emission computed tomography) using [123I]beta-CIT (2beta-carbomethoxy-3beta-[4-iodophenyl]tropane) as the radiotracer. Patients who were not currently being treated with these medications were given either 750 mg L-dopa/carbidopa per day (n = 8) or 10 mg L-selegiline per day (n = 8). [123I]beta-CIT imaging was performed three times in each patient: at baseline before treatment, while on medication and after 4-6 weeks of drug treatment, and following withdrawal from medication (approximately 1 week for L-dopa/carbidopa and 9 weeks for L-selegiline). Comparison of scans 2 and 3 provided a measure of drug occupancy of the [123I]beta-CIT binding site; comparison of scans 1 and 2 provided a measure of both up- or downregulation of DAT levels and drug occupancy following subchronic drug treatment. DAT levels were assessed from an image acquired approximately 22 hours after radiotracer injection as a ratio of regional brain activities: (striatum - occipital)/occipital. Striatal DAT levels were not significantly different when any two of the three scans were compared for both drug treatments. These results suggest that typical clinical doses of L-dopa/carbidopa and L-selegiline do not induce significant occupancy of the [123I]beta-CIT binding site and that 4-6 weeks of treatment causes no significant modulation of DAT levels. These results support the validity of measuring DAT levels with [123I]beta-CIT without the need to withdraw patients from medication treatment.

Aged↗
PubMed1999

No evidence of altered in vivo benzodiazepine receptor binding in schizophrenia.

Deficits in gamma-amino-butyric acid (GABA) neurotransmitter systems have been implicated in the pathophysiology of schizophrenia for more than two decades. Previous postmortem and in vivo studies of benzodiazepine (BDZ) receptor density have reported alterations in several brain regions of schizophrenic patients. The goal of this study was to better characterize possible alterations of the in vivo regional distribution volume (VT) of BDZ receptors in schizoprenia, using the selective BDZ antagonist [123I]iomazenil and single photon emission computerized tomography (SPECT). Regional BDZ VT was measured under sustained radiotracer equilibrium conditions. The reproducibility and reliability of this measurement was established in four healthy volunteers. No differences in regional BDZ VT were observed between 16 male schizophrenic patients and 16 matched controls. No relationships were observed between BDZ VT and severity of psychotic symptoms in any of the regions examined. In conclusion, this study failed to identify alterations of BDZ receptors density in schizoprenia. If this illness is associated with deficits in GABA transmission, these deficits do not substantially involve BDZ receptor expression or regulation.

Adult↗
PubMed1999

A complete remote-control system for reliable preparation of [18F]altanserin.

A complete remote control system was constructed for production of the PET 5-HT2A ligand [18F]altanserin by nitro-for-fluoro exchange. Comparing with published methods, the key features include (1) conducting azeotropic distillation and nucleophilic displacement in an open vessel heated by a commercial microwave oven; (2) purifying the product by a single HPLC procedure and (3) removing HPLC solvent by solid phase extraction. The preparation took 114 min with 23% yield and high quality.

Calibration↗
PubMed1999

Characterization of radioactive metabolites of 5-HT2A receptor PET ligand [18F]altanserin in human and rodent.

This study was performed to identify and characterize the radiometabolites of the serotonin 5-HT2A receptor ligand [18F]altanserin in supporting quantification of the target receptors by positron emission tomography. In analogy to its analog ketanserin, we postulated 4-(4-fluorobenzoyl)piperidine (FBP) and altanserinol for the previously observed two polar radiometabolites, corresponding to dealkylation at the piperidine nitrogen and reduction at the ketone, respectively. To test this hypothesis and characterize the in vivo and in vitro behavior of the radiometabolites, we synthesized nonradioactive authentic compounds altanserinol, 1-(4-fluorophenyl)-1-(piperidin-4-yl)methanol (FBPOH), and isolated nonradioactive FBP metabolite from monkey plasma. [18F]Altanserinol was obtained by NaBH4 reduction of [18F]altanserin, followed by acid hydrolysis. Identification of radiometabolites was carried out by high performance liquid chromatography and thin layer chromatography comparison of the radioactive plasma after injection of tracers with five authentic compounds. Human studies revealed that at least four radiometabolites, one identified as [18F]altanserinol, resulted from reduction of the ketone functionality. The N-dealkylation product [18F]FBP was not detectable; however, a radiometabolite of FBP was present in plasma after administration of [18F]altanserin. Monkey studies showed nonradioactive FBP was converted rapidly to a less polar metabolite. In rat, altanserin and altanserinol were converted to each other in vivo, and all the radiometabolites likely penetrated the blood-brain barrier and entered the brain. Displacement binding of altanserin to cloned serotonin 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors showed Ki values of 0.3, 6.0, 1,756, and 15 nM; the binding of FBP and altanserinol to these four 5-HT subtypes was negligible. We conclude from these studies that the radiometabolites of [18F]altanserin from N-dealkylation and ketone reduction should not interfere with specific receptor quantification in an equilibrium paradigm.

Animals↗
PubMed1999

Effects of vigabatrin on the GABAergic system as determined by [123I]iomazenil SPECT and GABA MRS.

PURPOSE: To evaluate effects of vigabatrin (VGB) by using [123I]iomazenil single-photon emission computed tomography (SPECT) to estimate central gamma-aminobutyric acid (GABA(A))/benzodiazepine receptors (BZRs), and magnetic resonance spectroscopy (MRS) to assess tissue GABA levels. METHODS: Six patients with partial seizures had both SPECT and MRS before and 25-84 days after starting VGB (3 g p.o., q.d.). SPECT was acquired by using the constant-infusion method and, after nonuniform attenuation correction, coregistered with T1-weighted MR Imaging (MRI) A volume of interest (VOI) of 3 x 2 x 2 cc over the occipital cortex, used for MRS acquisition, was positioned on both MRI and coregistered SPECT. Occipital activity was divided by either total plasma activity or plasma [123I]iomazenil concentration to estimate BZR distribution volume (V(T)-p and V'(T), respectively). Wilcoxon's test was used for VOI differences in GABA levels, BZR V(T)-p or V'(T). SPM96 (either no global normalization or proportional scaling) was used to compare BZR V(T)-p changes in the patients with and without VGB with test-retest data in eight healthy age-matched controls. RESULTS: Occipital GABA levels were increased threefold (without VGB, 1.1+/-0.1 micromol/g; with VGB, 2.9+/-0.5 micromol/g; p = 0.027). BZR distribution volumes showed no change, when estimated by either V(T)-p (without VGB, 6.00+/-0.91 ml/g; with VGB, 5.86+/-0.44 ml/g; p = 0.92) or V(T) (without VGB, 41.1+/-11.2 ml/g; with VGB, 41.2+/-9.9 ml/g; p = 0.75). No significant changes were detected by SPM96. CONCLUSIONS: A clinically effective dose of VGB caused a threefold increase in tissue GABA levels but was not associated with a substantial BZR downregulation.

Adult↗